These drugs decrease the effects of eicosanoids, mainly by blocking
the enzymatic activities of phospholipase A2, COX, or LOX
(Figure 34–2). A few drugs decrease the physiologic effects
of eicosanoids by inhibiting the binding of eicosanoids with LT
receptors. Aspirin, NSAIDs (including COX-2 inhibitors), and acetaminophen
are used to inhibit the formation of eicosanoids by inhibiting COX activity.
Glucocorticoids inhibit the formation of all eicosanoid products
by several mechanisms, including inhibition of phospholipase A2 activity.
Glucocorticoids are discussed in Chapter 23, and are briefly reviewed
under rheumatic diseases later in this chapter. Inhibitors of LOX
activity or LT receptors are used in the treatment of pulmonary
dysfunction, and are discussed in Chapter 35.
Aspirin (acetylsalicylic acid) is the prototype of the salicylates.
The other “traditional” nonselective NSAIDs (ibuprofen,
indomethacin, and many others) vary primarily in their potency and duration
of action (Table 34–2).
Table 34–2. Properties
of Aspirin and Some Nonsteroidal Anti-Inflammatory Drugs ||Download (.pdf)
Aspirin and the older nonselective NSAIDs inhibit all forms of
COX, and thereby decrease prostaglandin, prostacyclin, and thromboxane
synthesis throughout the body. Synthesis of prostaglandins necessary
for homeostatic function is disrupted, as is release of prostaglandins
involved in inflammation. The major difference between the mechanisms
of action of aspirin and other NSAIDs is that aspirin acetylates
and thereby irreversibly inhibits
COX. The other NSAIDs reversibly inhibit
COX. Salicylate is a metabolite of aspirin.
The pharmacokinetics of these drugs along with recommended anti-inflammatory
dosages are listed in Table 34–2.
Aspirin is readily absorbed and is hydrolyzed in blood and tissues
to acetate and salicylic acid. The half-life is 0.25 hour. Salicylate
is a reversible nonselective inhibitor of COX. Elimination of salicylate
is first order at low doses, with a half-life of 3 to 5 hours. At
high (anti-inflammatory) doses, half-life increases to 15 hours
or more and elimination becomes zero order. Excretion is via the
The other NSAIDs are well absorbed after oral administration. Ibuprofen has a half-life of about
2 hours, is relatively safe, and is the least expensive of the older,
nonselective NSAIDs. Naproxen is similar,
with a half-life of about 12 hours. Indomethacin is
a potent NSAID with increased toxicity. Oxaprozin and piroxicam are noteworthy because of
their longer half-lives (>50 hours), which permit less frequent
COX inhibitors reduce the manifestations of inflammation (their anti-inflammatory effect), although
they have no effect on underlying tissue damage or immunologic reactions. Prostaglandin
synthesis in the CNS is stimulated by pyrogens. NSAIDs suppress
this CNS prostaglandin synthesis, thus reducing fever (antipyretic effect). The pain relief
mechanism (analgesic effect) of these
agents is less well understood. Activation of peripheral nociceptors
may be diminished as a result of reduced production of prostaglandins
in injured tissue. In addition, a central COX mechanism is operative
which provides analgesia. Ibuprofen and naproxen have moderate anti-inflammatory
and analgesic efficacy. Other NSAIDs such as indomethacin have greater
anti-inflammatory effectiveness, whereas ketorolac has
greater analgesic efficacy. Aspirin and the nonselective NSAIDs
all have antiplatelet action (antithrombotic effect).
The prolonged antiplatelet action of aspirin, compared to the other
nonselective NSAIDs, results from the irreversible inhibition of
platelet COX-1. Thus, inhibition of thromboxane synthesis by aspirin
is essentially permanent in platelets because they lack the machinery
for new COX-1 synthesis. In contrast, in vascular endothelium, aspirin-mediated
inhibition of COX-2 and prostacyclin synthesis is temporary because
these cells can synthesize new COX-2. The irreversible platelet
action of aspirin results in a longer duration of its antiplatelet
effect compared to other NSAIDs. Aspirin and the nonselective NSAIDs
also interfere with the homeostatic functions of prostaglandins.
Most importantly, they reduce prostaglandin-mediated cytoprotection
in the gastrointestinal tract and autoregulation of renal function.
Aspirin and the nonselective NSAIDs have four main therapeutic
effects: anti-inflammatory, analgesic, antipyretic, and antithrombotic.
Aspirin has three oral optimal therapeutic dose ranges: The low
range (<300 mg/day) is effective in reducing platelet
aggregation; intermediate doses (600 to 650 mg/day) have
antipyretic and analgesic effects; and high doses (45 mg/kg/day
in divided doses) are used for the anti-inflammatory effect. Aspirin
and other NSAIDs are used to treat mild to moderate pain. This includes
musculoskeletal pain associated with inflammatory arthropathies
(rheumatoid arthritis, gout, and others) and pain associated with
osteoarthritis and musculoskeletal overuse injuries. Use of these
drugs for treatment of pain associated with osteoarthritis and musculoskeletal
overuse injuries exceeds use for inflammatory arthropathies. The
more frequent use of these drugs for osteoarthritis and musculoskeletal
overuse injuries is the result of their availability as over-the-counter
(OTC; i.e., without a prescription) products.
Aspirin and certain NSAIDs are also commonly used to treat nonmusculoskeletal
conditions such as dysmenorrhea, dental pain, and headache. For
severe pain, these drugs are often combined with opioid analgesics
(Chapter 20). In infants with patent ductus arteriosus, closure
of a patent ductus arteriosus in an otherwise normal infant can
be accelerated with an NSAID such as indomethacin or ibuprofen.
Owing to aspirin’s irreversible inhibition of COX and its
effects on platelet function, it is the optimal antithrombotic drug
to minimize the risk of coronary occlusion and heart attacks (Chapter 11). Long-term use of NSAIDs also reduces the risk of colon cancer.
Ketorolac is used mainly as a systemic analgesic and not as an
anti-inflammatory drug (although it has typical nonselective NSAID
The most common adverse effect from therapeutic anti-inflammatory
doses of aspirin is gastric upset. Chronic use can result in gastric
ulceration, upper gastrointestinal bleeding, and renal effects,
including acute tubular necrosis and interstitial nephritis. Aspirin
increases the bleeding time owing to its antiplatelet effect. When
prostaglandin synthesis is inhibited by even small doses of aspirin,
persons with aspirin hypersensitivity may experience asthma. Research
suggests that some cases of aspirin allergy result from diversion
of arachidonic acid to the leukotriene pathway when the cyclooxygenase-catalyzed
prostaglandin pathway is blocked. The resulting increase in leukotriene
synthesis causes the bronchoconstriction that is typical of aspirin
allergy. For unknown reasons, this form of aspirin allergy is more
common in individuals with nasal polyps. This type of hypersensitivity
to aspirin precludes treatment with any NSAID.
At higher doses of aspirin, tinnitus, vertigo, hyperventilation,
and respiratory alkalosis are observed. At very high doses, the
drug causes metabolic acidosis, dehydration, hyperthermia, collapse,
coma, and death. Children with viral infections are at increased
risk for Reye’s syndrome (hepatic fatty degeneration and
encephalopathy) if they are given aspirin.
Concomitant administration of nonselective NSAIDs with aspirin
may diminish the irreversible platelet inhibition induced by aspirin.
This is because both drugs compete for COX-1 in the platelet. Binding
of the reversible NSAID to COX-1 prevents aspirin from binding
and irreversibly inhibiting the enzymatic site. To avoid this interaction
between aspirin and the other NSAIDs, dosing recommendations are
to take the aspirin, for its antiplatelet effect, a minimum of 1
hour prior to taking any of the other nonselective NSAIDs.
Like aspirin, these agents are associated with significant gastrointestinal
disturbance, but the incidence is lower than with aspirin. There
is a risk of renal damage with any of the NSAIDs, especially in
patients with preexisting renal disease. Because these drugs are
cleared by the kidney, renal damage results in higher, more toxic
serum concentrations. Use of parenteral ketorolac is generally restricted
to 72 hours because of the risk of gastrointestinal and renal damage
with longer administration. Serious hematologic reactions have been
noted with indomethacin. In 2005, the Food and Drug Administration (FDA) requested that all prescriptions
of NSAIDs contain a warning about the increased risk of serious
adverse cardiovascular events associated with these drugs. The OTC
use of these drugs was not required to have a similar warning because
OTC dosages are lower.
Celecoxib,rofecoxib, and valdecoxib are members of the COX-2–selective
inhibitors class. Theoretically, COX-2–selective inhibitors should
have less effect on the prostaglandins involved in homeostatic function,
particularly those in the gastrointestinal tract. These drugs have
analgesic, antipyretic, and anti-inflammatory effects similar to
those of the nonselective NSAIDs. Celecoxib is the only COX-2 inhibitor
currently available in the United States (Table 34–2) because
increased cardiovascular risks were reported for rofecoxib (see
below under toxicity).
COX-2 inhibitors are primarily used in inflammatory disorders.
Nonselective NSAIDs and COX-2–selective drugs also reduce
polyp formation in the colon in patients with primary familial adenomatous
The COX-2–selective inhibitors have demonstrated a reduced
risk of gastrointestinal effects, including gastric ulcers and serious
gastrointestinal bleeding. They are not recommended in renal dysfunction
because COX-2 is constitutively active in the kidney. Celecoxib
is a sulfonamide and may cause a hypersensitivity reaction in patients
who are allergic to other sulfonamides. In contrast to nonselective
COX inhibitors (aspirin and nonselective NSAIDs), COX-2 inhibitors
do not reduce platelet aggregation and they lack antithrombotic
activity. Thus, COX-2 inhibitors offer no protection in patients
at high-risk of myocardial infarction or stroke. Clinical investigations
have documented an increased risk
of adverse cardiovascular events in patients medicated with certain
COX-2 inhibitors. This increased risk is not equivalent across the
spectrum of COX-2 inhibitors and resulted in two of these COX-2
inhibitors (rofecoxib and valdecoxib) being voluntarily withdrawn
from the market in the United States by their manufacturers.
The inhibition of COX-1 compared to COX-2 by aspirin, nonselective
NSAIDs, and COX-2 inhibitors is relative and varies with the drug.
Celecoxib selectivity for inhibiting COX-2 is 10 to 20 times that
for COX-1. Meloxicam and etodolac
are included with the nonselective NSAIDs in this chapter (Table
34–2); however, both of these NSAIDs have a slightly higher
selectivity for COX-2 compared to COX-1. In contrast, a number of
the nonselective NSAIDs inhibit both COX-1 and COX-2 equally (diclofenac, flurbiprofen,
ibuprofen, indomethacin, ketoprofen, meclofenamate, piroxicam, tenoxicam,
Acetaminophen does not fall into any of the previous drug classifications,
and is available in the United States without prescription. Phenacetin
is a toxic prodrug that is metabolized to acetaminophen, and is
still available in some other countries.
Action and Physiologic Effects
Acetaminophen is an analgesic and antipyretic agent lacking anti-inflammatory
or antithrombotic effects. The mechanism of analgesic action of
acetaminophen is unclear. The drug is only a weak COX-1 and COX-2
inhibitor in peripheral tissues, which accounts for its lack of
anti-inflammatory effect. Some evidence suggests that acetaminophen
inhibits a CNS COX isozyme that accounts for its analgesic and antipyretic
and Clinical Use
Acetaminophen is effective for the same indications as intermediate-dose
aspirin. Acetaminophen is, therefore, useful as an aspirin substitute,
especially in children with viral infections and in individuals
with any type of aspirin intolerance. Acetaminophen is well absorbed
orally and metabolized in the liver. The half-life is 2 to 3 hours
in persons with normal hepatic function and the half-life is unaffected
by renal disease.
In therapeutic dosages, acetaminophen has negligible toxicity
in most individuals. However, when taken in overdose or by patients
with severe liver impairment, the drug is a dangerous hepatotoxin.
The mechanism of toxicity requires oxidation to cytotoxic intermediates
by phase I cytochrome P450 enzymes. This occurs if substrates for
phase II conjugation reactions (acetate and glucuronide) are lacking
(Chapter 3). People who regularly consume three or more alcoholic drinks
per day are at increased risk of acetaminophen-induced hepatotoxicity
(Chapters 3 and 21).